WO2008156573A1 - Inhibiteurs de kinases, leurs compositions et procédés d'utilisation - Google Patents

Inhibiteurs de kinases, leurs compositions et procédés d'utilisation Download PDF

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WO2008156573A1
WO2008156573A1 PCT/US2008/007181 US2008007181W WO2008156573A1 WO 2008156573 A1 WO2008156573 A1 WO 2008156573A1 US 2008007181 W US2008007181 W US 2008007181W WO 2008156573 A1 WO2008156573 A1 WO 2008156573A1
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substituted
unsubstituted
compound
alkyl
diabetes
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PCT/US2008/007181
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Robert Shoemaker
John Cardellina
Michael Currens
Sudhir Kondapaka
Yves Pommier
Andy Jobson
Dominic Scudiero
David Waugh
George Lountos
Charles M. Cook
Guangtao Zhang
Andrew Colasanti
Christopher R. Self
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Provid Pharmaceuticals, Inc.
The United States Of America As Represented By The Department Of Health And Human Services, Nih
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Priority to AU2008267081A priority Critical patent/AU2008267081B2/en
Priority to CA2690410A priority patent/CA2690410C/fr
Priority to EP08768252.2A priority patent/EP2155675B1/fr
Publication of WO2008156573A1 publication Critical patent/WO2008156573A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/86—Hydrazides; Thio or imino analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/52—Nitrogen atoms not forming part of a nitro radical with hetero atoms directly attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/50—Nitrogen atoms bound to hetero atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • FIELD Provided herein are certain guanidinyl hydrazone-substituted compounds and derivatives, compositions comprising such compounds and methods for treating or preventing cancer, hypoxia, diabetes, stroke, autoimmune disease or a disease, disorder or condition treatable or preventable by inhibition of Chk2, the ATM-Chk2 pathway or RSK2. comprising administering a compound disclosed herein to a patient.
  • Cellular checkpoints are molecular pathways which are activated in response to DNA damage, such as DNA double-strand breaks (DSB). Pommier et al, 2005, Current Pharmaceutical Design 11:2855-2872. Modulation of these checkpoints can kill damaged cells via apoptosis or arrest cell cycle progression allowing for DNA repair prior to cellular reproduction, thus preventing or slowing tumor progression. Id. The ATM-Chk2 pathway, which is primarily activated by DSB, is thought to play a key role in apoptosis and cell cycle arrest. Id. Chk2 has emerged as an important multifunctional player in the DNA-damage response signalling pathway. Antoni et al. , 2007, Nat. Rev. Can. 7(12):925-936.
  • the level of intrinsic DNA damage in a given tumor cell and the degree to which Chk2 functions are essential for maintenance of the transformed phenotype of the cell can guide the use of Chk2 inhibitors against the tumor.
  • a Chk2 inhibitor could have potential for single-agent efficacy.
  • a combination of a Chk2 inhibitor with a DNA-damaging agent might be more useful.
  • RSK2 is a serine/threonine kinase involved in cell signaling which is activated by ERK and PDKl (Kang et al, 2007, Cancer Cell. 12(3):20l- ⁇ 4).
  • ERK and PDKl serine/threonine kinase involved in cell signaling which is activated by ERK and PDKl.
  • Several investigators have found evidence for a role of RSK2 in malignant transformation (Cho et al, 2007, Cancer Res. (17):8104-12; David et al, 2005, J CHn Invest. 115 (3) :664-72). Clark et al.
  • RSK2 has shown a role for RSK2 in regulation of prostate cancer growth and reported a novel inhibitor as a potential therapeutic lead (Clark et al. , 2005, Cancer Res. 65(8):3108-16). Their work provides a strong rational for targeting RSK2 in prostate cancer.
  • RSK2 appears to be essential for certain aspect of normal lymphocyte activation (Lin et al, 2008, Blood lll(2):525-33).
  • an inhibitor could have an anti-viral effect (Kuang et al, 2008, J Virol 52 ⁇ :1838-50).
  • RSK2 inhibitors have also been described by Cohen et al.
  • a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer each being referred to herein as a "Compound" for treating or preventing cancer, hypoxia, diabetes, stroke, autoimmune disease or a disease, disorder or condition treatable or preventable by inhibition of Chk2 or the ATM-Chk2 pathway.
  • compositions comprising a Compound, and compositions (e.g., pharmaceutical compositions) comprising a Compound and a pharmaceutically acceptable carrier, vehicle or diluent.
  • compositions for treating or preventing cancer, hypoxia, diabetes, stroke, autoimmune disease or a disease, disorder or condition treatable or preventable by inhibition of Chk2 or the ATM-Chk2 pathway.
  • methods for preventing or reducing apopstosis in a normal cell in a patient comprising identifying a patient having one or more cells in need of such prevention or reduction and administering to the patient an amount of a Compound effective to prevent or reduce apoptosis in a normal cell.
  • methods for sensitizing a tumor, a cancer cell or cancerous tissue to an anticancer agent, anticancer treatment or a DNA targeted agent comprising administering a patient who has cancer or a tumor an amount of a Compound effective to sensitize the cancer or tumor to an anticancer agent, anticancer treatment or a DNA targeted agent.
  • Chk2 phosphorylation in a patient (e.g., in a patient's cell(s)), comprising administering to the patient an amount of a Compound effective to modulate Chk2 phosphorylation.
  • Chk2 phosphorylation is inhibited or down-regulated.
  • a patient is identified as being in need of such modulation through a screening assay prior to such administration.
  • the Compound targets two or more of the following: kinases from the Chk kinase family, kinases from the MEK kinase family, kinases from the src kinase family, kinases from the RSK kinase family (e.g., RSK2), kinases from the CDK family, kinases from the MAPK kinase family, and tyrosine kinases such as Fes, Lyn, and Syk kinases.
  • the Compound may target two or more kinases of the same family, or may target kinases representing two or more kinase families or classes.
  • particularly useful Compounds include those which can abrogate DNA damage-induced Chk2 autophosphorylation on S516, abrogate DNA damage-induced HDMX degradation, abrogate Chk2 -mediated IR-induced apoptosis in mouse thymocytes and provide or promote synergism of DNA damaging agents in human cancer cells.
  • the figures set forth herein provide direct and indirect measurements of Chk2 inhibition and provide such functional endpoints for Compounds.
  • TPT tumor necrosis factor
  • BHT29 cells were treated with Compounds (25 ⁇ M) for 1 hour. Following this the cells were exposed to 10 Gy IR and incubated for a further hour. Whole cell extracts were made and Western blotting for Chk2 S516 was performed. Asterisks indicate non-specific band running slightly slower than Chk2 S516. This data demonstrates that Compounds are useful for the treatment of cancer, either alone or in combination with other anti-cancer agents or therapies (e.g., chemotherapy or radiation therapy).
  • FIG. Abrogation of HDMX degradation by compound 18 in MCF7 cells following DNA damage.
  • MCF7 cells were treated in the absence (control) or presence of compound 18 at varying concentrations for 2.5 hours. The cells were then exposed to either 1 ⁇ M topotecan (TPT) for 4 hours or they were exposed to 10 Gy IR and incubated for 4 hours. Whole cell extracts were made and Western blotting was performed to detect HDMX. The levels of HDMX were quantified from the blots and normalized to actin. The normalized levels of HDMX are depicted as bar graphs under the blots. This data demonstrates that Compounds are useful for the treatment of cancer, either alone or in combination with other anti-cancer agents or therapies.
  • FIG 3. Compound 18-mediated abrogation of IR-induced apoptosis in mouse thymocytes.
  • Thymocytes were isolated from Chk2 +/+ or Chk2 -/- mice by mechanical disaggregation. The isolated thymocytes were treated in the absence or presence of 1 ⁇ M compound 18 or ref* (J. Wu et al, Bioorganic and Medicinal Chemistry letters, 2007, 17(1), 172 ,[ N-isobutyl analog of compound 7]) for 1 hour. The cells were then exposed to 5 Gy IR and incubated for 16 hours. The cells were then washed in PBS and fixed in ethanol.
  • PI Propidium isodide
  • CPT camptothecin
  • OVCAR-4 cells OVCAR-4 cells.
  • OVCAR-4 cells were treated with either compound 18 or CPT as single agents in 96 well tissue culture plates. In addition, the cells were exposed to 40 combinations of compound 18 and CPT. The drug treatments were for 48 hours and the cells were then subjected to MTS staining to determine the growth inhibitory effect.
  • the graph represents a 3-dimensional plot of the MTS data obtained.
  • the upper, light gray surface represents a theoretical surface of additivity that was generated from dose response curves of compound 18 alone and CPT alone.
  • the lower, dark grey surface depicts the surface of the combination of compound 18 and CPT that was generated from data obtained in the MTS assay (shown by the blue circles). Data points lying under the green additivity surface are deemed to synergistic combinations.
  • the bar graph on the right is a 2-dimensional representation of 1 combination of 11 ⁇ M compound 18 and 6.25 ⁇ M CPT taken from the 3-D model. This data demonstrates that Compounds are useful for the treatment of cancer, either alone or in combination with other anti-cancer agents or therapies. 5.2 DEFINITIONS
  • a "C 1-6 alkyl” group is a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms.
  • Representative C 1-6 alkyl groups or radicals include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl; -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, - isopentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3- dimethylbutyl and the like.
  • a C 1-6 alkyl group can be substituted or unsubstituted.
  • a "C 1-6 alkylene” group is a saturated straight chain or branched non-cyclic hydrocarbon linker having from 1 to 6 carbon atoms.
  • C 1-6 alkylene groups include, but are not limited to, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 - and -(CH 2 ) 6 -.
  • a C 1-6 alkylene group can be substituted or unsubstituted.
  • a " C 3-10 cycloalkyl” group is a cyclic alkyl group of from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed or bridged rings which can be unsubstituted or substituted with from 1 to 3 alkyl groups.
  • Such C 3-10 cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1 -methyl cyclopropyl, 2- methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple or bridged ring structures such as adamantanyl and the like.
  • a C 3-10 cycloalkyl group can be substituted or unsubstituted.
  • Such substituted C 3-10 cycloalkyl groups include, by way of example, cyclohexanone and the like.
  • a "5- or 6-membered cycloalkenyl” ring is an unsaturated cyclic alkenyl group of from 5 to 6 carbon atoms having one or more double bonds. Such groups include, by way of example, cyclopentene, cyclohexene, and the like. The double bond can be shared with an aryl (e.g., phenyl) group when the 5- or 6-membered cycloalkenyl ring is fused to an aryl (e.g., phenyl) group.
  • a 5- or 6-membered cycloalkenyl ring can be substituted or unsubstituted.
  • a "carboxyl” or “carboxy” is a -COOH group.
  • a "C 3-10 heteroaryl” group is an aryl ring system having one to four heteroatoms as ring atoms in a heteroaromatic ring system, wherein the remainder of the atoms are carbon atoms. Suitable heteroatoms include oxygen, sulfur and nitrogen. In certain embodiments, the heterocyclic ring system is monocyclic or bicyclic. Non-limiting examples include aromatic groups selected from the following:
  • C 3-10 heteroaryl groups include, but are not limited to, benzofuranyl, benzothienyl, indolyl, benzopyrazolyl, coumarinyl, furanyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, thiophenyl, pyrimidinyl, isoquinolinyl, quinolinyl, pyridinyl, pyrrolyl, pyrazolyl, 1H-indolyl, 1H-indazolyl, benzo[d]thiazolyl, 1H- benzo[d]imidazole and pyrazinyl.
  • C 3-10 heteroaryls can be bonded at any ring atom (i.e., at any carbon atom or heteroatom of the C 3-10 heteroaryl ring)
  • a C 3-10 heteroaryl group can be substituted or unsubstituted.
  • a "C 3-10 heterocycloalkyl” group is a non-aromatic cycloalkyl in which one to four of the ring carbon atoms are independently replaced with a heteroatom from the group consisting of O, S and N.
  • C 3-10 heterocycloalkyl groups include, but are not limited to, morpholinyl, pyrrolidinyl, piperizinyl, (1,4)-dioxane, (1,3)-dioxolane, and 4,5-dihydro-1H-imidazolyl.
  • C 3-10 heterocycloalkyls can be bonded at any ring atom (i.e., at any carbon atom or heteroatom of the C M oheterocycloalkyl ring).
  • a C 3- ioheterocycloalkyl group can be substituted or unsubstituted.
  • substituted they may be substituted with any suitable substituent.
  • the term "pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base.
  • a Compound contains an acidic or basic moiety, it can be provided as a pharmaceutically acceptable salt (See, Berge et al., J Pharm. Sci. 1977, 66, 1-19; and "Handbook of Pharmaceutical Salts, Properties, and Use,” Stah and Wermuth, Ed.; Wiley-VCH and VHCA, Zurich, 2002).
  • Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(lS)- camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, gluco
  • Suitable bases for use in the preparation of pharmaceutically acceptable salts including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, l-(
  • solvate means an a Compound, or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • solvate means an a Compound, or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • stereoisomer or
  • stereomerically pure means one stereoisomer of a Compound that is substantially free of other stereoisomers of that compound.
  • the stereoisomer is an enantiomer or diastereomer.
  • a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
  • a stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
  • the Compounds can have chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof.
  • Various Compounds contain one or more chiral centers, and can exist as racemic mixtures of enantiomers, mixtures of diastereomers or enantiomerically or optically pure compounds.
  • the use of stereomerically pure forms of such Compounds, as well as the use of mixtures of those forms are encompassed by the embodiments disclosed herein.
  • mixtures comprising equal or unequal amounts of the enantiomers of a particular Compound may be used in methods and compositions disclosed herein.
  • These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et ah, Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al, Tetrahedron
  • the Compounds can include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof. In certain embodiments, the Compounds are isolated as either the E or Z isomer. In other embodiments, the Compounds are a mixture of the E and Z isomers.
  • R includes the tautomer , and the structure includes the tautomer
  • the term "effective amount" in connection with a Compound can mean an amount capable of treating or preventing a disease disclosed herein, such as cancer, a precancerous lesion, hypoxia, diabetes, stroke, autoimmune disease or a condition treatable or preventable by inhibition of Chk2, the ATM-Chk2 pathway or RSK2.
  • a disease disclosed herein such as cancer, a precancerous lesion, hypoxia, diabetes, stroke, autoimmune disease or a condition treatable or preventable by inhibition of Chk2, the ATM-Chk2 pathway or RSK2.
  • the term "patient” includes an animal, including, but not limited to, an animal such a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig, in one embodiment a mammal, in another embodiment a human.
  • the patient is an animal, such as a human, in need of the treatment or prevention of cancer, hypoxia, diabetes, stroke, autoimmune disease or a disease, disorder or condition treatable or preventable by inhibition of Chk2, the ATM-Chk2 pathway or RSK2.
  • n is an integer selected from 0 and 1 ;
  • R 1 is H;
  • R 2 is -C(O)H, -C(O)C 1-6 alkyl, -OC 1-6 alkyl or a group selected from:
  • X is -N(R 4 )-C(O)-N(R 4 )-, -C(O)-N(R 4 )-, -N(R 4 )-C(O)-, -N(R 4 )-N(R 4 )-C(O)-,
  • L is a direct bond or C 1-6 alkylene
  • A is substituted or unsubstituted aryl, substituted or unsubstituted C 3- l oheteroaryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3- l oheterocycloalkyl, or substituted or unsubstituted C 1-6 alkyl;
  • R 3 is at each occurrence independently H, -OH, -OC 1-6 alkyl, -NH 2 , -NHOH, -
  • R 4 , R 5 and R 6 are at each occurence independently H, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 heteroaryl, substituted or unsubstituted
  • the Compounds of formula (I) are those wherein ring B
  • the Compounds of formula (I) are those wherein A is aryl substituted with one or more substituents other than C 1-6 alkyl, halo or alkoxy, substituted or unsubstituted C 3-10 heteroaryl, substituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycloalkyl, or substituted C 1-6 alkyl.
  • the Compounds of formula (I) are those wherein A is substituted aryl, wherein the aryl group has 2-5 substituents (e.g., 2-5 substituents selected from substituents set forth herein).
  • the Compounds of formula (I) are those wherein A is substituted or unsubstituted IH- indole, substituted or unsubstituted 1H-indazole, substituted or unsubstituted benzofuran or substituted or unsubstituted benzo[ ⁇ f]thiazole.
  • the Compounds of formula (I) are those wherein R is ⁇ .
  • R and R 5 are as described above.
  • R is H and R 2 is , wherein R 3 and R 5 are as described above.
  • the Compounds of formula (I) are those wherein X is -C(O)-N(R 4 )- or -N(R 4 )-C(O)-, wherein R 4 is as described above.
  • the Compounds of formula (I) are those wherein L is a direct bond.
  • the Compounds of formula (I) are those wherein R 5 is H, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 heteroaryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3- l oheterocycloalkyl, or substituted or unsubstituted C 3-6 alkyl.
  • the Compounds of formula (I) are those wherein R 5 is C 1-6 alkyl. [0084] In another embodiment, the Compounds of formula (I) are those wherein R is H.
  • the Compounds of formula (I) are those wherein A is substituted aryl. [0086] In another embodiment, the Compounds of formula (I) are those wherein A is substituted or unsubstituted C 3-10 heteroaryl. [0087] In another embodiment, the Compounds of formula (I) are those wherein A is
  • L is a direct bond or C 1-6 alkylene
  • A is substituted or unsubstituted aryl, substituted or unsubstituted C 3- l oheteroaryl, substituted or unsubstituted C 3-
  • the Compounds of formula (II) are those wherein A is aryl substituted with one or more substituents other than C 1-6 alkyl, halo or alkoxy, substituted or unsubstituted C 3-10 heteroaryl, substituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycloalkyl, or substituted C 1-6 alkyl.
  • the Compounds of formula (II) are those wherein A is: phenyl substituted with halogen, C 1-6 alkyl, C(O)C 1-6 alkyl, CN, urea or pyrimidine; unsubstituted C 3-10 heteroaryl; C 3-10 heteroaryl substituted with NH 2 , NO 2 , OH, halogen, C 1-
  • the Compounds of formula (II) are those wherein A is substituted aryl, wherein the aryl group has 2-5 substituents (e.g., 2-5 substituents selected from substituents set forth herein).
  • the Compounds of formula (II) are those wherein A is substituted or unsubstituted 1H-indole, substituted or unsubstituted 1H-indazole, substituted or unsubstituted benzofuran or substituted or unsubstituted benzo[d]thiazole.
  • the Compounds of formula (II) are those wherein R 5 is ⁇ , substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 heteroaryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3- l oheterocycloalkyl, or substituted or unsubstituted C 3-6 alkyl.
  • the Compounds of formula (II) are those wherein R 5 is C 1-6 alkyl.
  • the Compounds of formula (II) are those wherein R 5 is ⁇ .
  • the Compounds of formula (II) are those wherein A is substituted aryl.
  • the Compounds of formula (II) are those wherein A is substituted or unsubstituted C 3-10 heteroaryl.
  • the Compounds of formula (II) are those wherein X is -N(R 4 )-C(O)-N(R 4 )-, wherein R 4 is as described above.
  • the Compounds of formula (II) are those wherein X is -C(O)-N(R 4 )- or -N(R 4 )-C(O)-, wherein R 4 is as described above.
  • the Compounds of formula (II) are those wherein R is C 1-6 alkyl and A is substituted aryl.
  • A is substituted or unsubstituted aryl, substituted or unsubstituted C 3- l oheteroaryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3- l oheterocycloalkyl, or substituted or unsubstituted C 1-6 alkyl; and [00110] R 5 is H, substituted or unsubstituted aryl, substituted or unsubstituted C 3- l ⁇ heteroaryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3- l oheterocycloalkyl, or substituted or unsubstituted C 1-6 alkyl.
  • the Compounds of formula (III) are those wherein A is aryl substituted with one or more substituents other than C 1-6 alky!, halo or alkoxy, substituted or unsubstituted C 3-10 heteroaryl, substituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycloalkyl, or substituted C 1-6 alkyl.
  • the Compounds of formula (III) are those wherein A is: phenyl substituted with halogen, C 1-6 alkyl, C(O)C 1-6 alkyl, CN, urea or pyrimidine; unsubstituted C 3-10 heteroaryl; C 3 _ 10 heteroaryl substituted with NH 2 , NO 2 , OH, halogen, C 1-
  • the Compounds of formula (III) are those wherein A is substituted aryl, wherein the aryl group has 2-5 substituents (e.g., 2-5 substituents selected from substituents set forth herein).
  • the Compounds of formula (III) are those wherein A is substituted or unsubstituted 1H-indole, substituted or unsubstituted 1H-indazole, substituted or unsubstituted benzofuran or substituted or unsubstituted benzo[d]thiazole.
  • the Compounds of formula (III) are those wherein R 5 is H, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 heteroaryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3- l oheterocycloalkyl, or substituted or unsubstituted C 3-6 alkyl.
  • the Compounds of formula (III) are those wherein R 5 is C 1-6 alkyl.
  • the Compounds of formula (III) are those wherein R 5 is H.
  • the Compounds of formula (III) are those wherein A is substituted aryl.
  • the Compounds of formula (III) are those wherein A is substituted or unsubstituted C 3-10 heteroaryl.
  • the Compounds of formula (III) are those wherein R 5 is C 1-6 alkyl and A is substituted aryl. [00121] In another embodiment, the Compounds of formula (III) are those wherein A
  • the Compounds of formulas (I)-(HI) do not include compounds wherein A is phenyl substituted with halogen, alkoxy, or C 1-6 alkyl.
  • the Compounds of formulas (I)-(III) do not include compounds wherein A is phenyl substituted with a secondary or tertiary amine.
  • the Compounds of formulas (I)-(III) do not include compounds wherein A is unsubstituted phenyl.
  • the Compounds of formulas (I)-(III) do not include compounds wherein A is unsubstituted cyclohexyl. [00134] In another embodiment, the Compounds of formulas (I)-(III) do not include compounds wherein A is acetyl.
  • the Compounds of formulas (I)-(III) do not include compounds wherein A possesses a urea moiety.
  • R 1 is H
  • R 2 is -C(O)H, -C(O)C ,. 6 alkyl or a group selected from:
  • R 1 and R 2 taken together with the atoms to which they are attached form a substituted or unsubstituted 5- or 6- membered cycloalkenyl ring;
  • X is -N(R 4 )-C(O)-N(R 4 )-, -C(O)-N(R 4 )-, -N(R 4 )-C(O)-, -N(R 4 )-N(R 4 )-C(O)-,
  • L is a direct bond or C 1-6 alkylene
  • A is substituted or unsubstituted C 3-10 heteroaryl; [00144] R 3 is at each occurrence independently -NH 2 , -NHOH, -NHR 6 , -SH or -S-C 1-
  • R 4 , R 5 and R 6 are at each occurence independently H, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 heteroaryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycloalkyl, or substituted or unsubstituted C 1-6 alkyl,
  • R 2 is one of the following groups:
  • R 1 and R 2 taken together with the atoms to which they are attached form a substituted or unsubstituted 5- or 6-membered cycloalkenyl ring;
  • X is -N(R 4 )-C(O)-N(R 4 )-, -C(O)-N(R 4 )-, -N(R 4 )-C(O)-, -N(R 4 )-N(R 4 )-C(O)-,
  • L is a direct bond or C 1-6 alkylene
  • A is substituted or unsubstituted aryl substituted or unsubstituted C 3- loheteroaryl, substituted or unsubstituted C stituted or unsubstituted C 3- 10 heterocycloalkyl, or substituted or unsub and [00153] R 4 is H, substituted or unsubstituted aryl, substituted or unsubstituted C 3- loheteroaryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3- loheterocycloalkyl, or substituted or unsubstituted C 1-6 alkyl, [00154] wherein A is substituted with at least one group selected from:
  • R 3 is at each occurrence independently -NH 2 , -NHOH, -NHR 6 , -SH or -S-Cj- 6 alkyl;
  • R 5 and R 6 are at each occurence independently H, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 heteroaryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycloalkyl, or substituted or unsubstituted C 1-6 alkyl.
  • the Compounds of formula (V) are those wherein
  • the Compounds of formula (V) are those wherein A is substituted aryl, wherein the aryl group has 2-5 substituents (e.g., 2-5 substituents selected from substituents set
  • the Compounds of formula (V) are those wherein A is substituted or unsubstituted 1H-indole, substituted or unsubstituted 1H-indazole, substituted or unsubstituted benzofuran or substituted or unsubstituted benzo[J]thiazole.
  • the Compounds of formula (V) are those wherein R 1 is ⁇ .
  • the Compounds of formula (V) are those wherein R 1 and R 2 taken together with the atoms to which they are attached form substituted 5- membered cycloalkenyl ring.
  • the Compounds of formula (V) are those wherein R 1 and R 2 taken together with the atoms to which they are attached form substituted 6- membered cycloalkenyl ring.
  • the Compounds of formula (V) are those wherein X is -N(R 4 )-C(O)-N(R 4 )-, wherein R 4 is as described above.
  • the Compounds of formula (V) are those wherein X is -C(O)-N(R 4 )- or -N(R 4 )-C(O)-, wherein R 4 is as described above.
  • the Compounds of formula (V) are those wherein L is a direct bond.
  • the Compounds of formula (V) are those wherein X is -N(R 4 )-C(O)-N(R 4 ) and L is a direct bond, wherein R 4 is as described above.
  • the Compounds of formula (V) are those wherein R 4 is ⁇ . [00169] In another embodiment, the Compounds of formula (V) are those wherein A is substituted aryl.
  • the Compounds of formula (V) are those wherein A is substituted or unsubstituted C 3-10 heteroaryl.
  • R 2 is -C(O)C i -6 alkyl or a group selected from:
  • X is -N(R 4 )-C(O)-N(R 4 )-, -C(O)-N(R 4 )-, -N(R 4 )-C(O)-, -N(R 4 )-N(R 4 )-C(O)-,
  • L is a direct bond or C 1-6 alkylene;
  • A is substituted or unsubstituted C 3-10 heteroaryl, aryl mono substituted with halogen, cyano, NH 2 , NO 2 , OH, C 1-6 alkyl, alkoxy, -C(O)C 1-6 alkyl, -N(R 4 )-C(O)-N(R 4 )- or a
  • R 3 is at each occurrence independently -NH 2 , -NHOH, -NHR 6 , -SH or -S-C 1- ealkyl;
  • R 4 , R 5 and R 6 are at each occurence independently H, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 heteroaryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycloalkyl, or substituted or unsubstituted C 1-6 alkyl; and [00179] R 7 is substituted or unsubstituted C 3-6 alkyl,
  • R 2 is one of the following groups:
  • X is -N(R 4 )-C(O)-N(R 4 )-, -C(O)-N(R 4 )-, -N(R 4 )-C(O)-, -N(R 4 )-N(R 4 )-C(O)-,
  • L is a direct bond or C 1-6 alkylene
  • A is substituted or unsubstituted aryl, substituted or unsubstituted C 3- loheteroaryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3- 10 heterocycloalkyl, or substituted or unsubstituted C 1-6 alkyl;
  • R 2 is
  • R 3 is at each occurrence independently H, -OH, -OC 1-6 alkyl, -NH 2 , -NHOH, -
  • R 5 is H, substituted or unsubstituted aryl, substituted or unsubstituted C 3- loheteroaryl, substituted or unsubstituted C 3- ⁇ ocycloalkyl, substituted or unsubstituted C 3- loheterocycloalkyl, or substituted or unsubstituted C 1-6 alkyl.
  • the Compounds of formula (VII) are those wherein X is
  • R is , wherein R is substituted or unsubstituted C 1-6 alkyl.
  • the Compounds of formula (VII) are those wherein
  • R 2 is , wherein R 5 is substituted or unsubstituted
  • A is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
  • VIII Compounds of formula (VIII):
  • R 3 is at each occurrence independently H, -OH, -OC 1-6 alkyl, -NH 2 , -NHOH,
  • R 5 is H, substituted or unsubstituted aryl, substituted or unsubstituted C 3- l oheteroaryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3- l oheterocycloalkyl, or substituted or unsubstituted C 1-6 alkyl.
  • the Compounds of formula (VIII) are those wherein R 5 is substituted or unsubstituted C 1-6 alkyl, such as methyl.
  • R 3 is NH 2 or OH.
  • R 3 is NH 2 or H.
  • Rs is substituted or unsubstituted C 1-6 alkyl, such as methyl, and R 3 is NH 2 or H.
  • R 2 is or -OC 1-6 alkyl
  • R 3 is at each occurrence independently H, -OH, -OC 1-6 alkyl, -NH 2 , -NHOH, ⁇
  • R 5 is H, substituted or unsubstituted aryl, substituted or unsubstituted C 3- l oheteroaryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3- l oheterocycloalkyl, or substituted or unsubstituted C 1-6 alkyl.
  • the Compounds of formula (IX) are those wherein R 5 is substituted or unsubstituted C 1-6 alkyl, such as methyl.
  • the Compounds of formula (IX) are those wherein R 3 is NH 2 or OH.
  • R 3 is NH 2 or H.
  • R 5 is substituted or unsubstituted C 1-6 alkyl, such as methyl, and R 3 is NH 2 or H.
  • Representative Compounds are set forth in Table 1, below. Table 1
  • Compounds target two or more of the following: kinases from the Chk kinase family, kinases from the MEK kinase family, kinases from the src kinase family, kinases from the RSK kinase family, kinases from the CDK family, kinases from the MAPK kinase family, and tyrosine kinases such as Fes, Lyn, and Syk kinases.
  • Compounds may target two or more kinases of the same family, or may target kinases representing two or more kinase families or classes. Compounds may also target kinases with differing potencies.
  • the Compound is selective for Chk2 over Chkl (i.e., modulates or inhibits Chk2 activity without significantly modulating or inhibiting Chkl activity).
  • compounds selective for targeting Chk2 over Chkl are particularly useful as therapeutic agents because the Chk2 pathway is activated first and transiently following DNA damage whereas the Chkl pathway is activated secondarily and in a more sustained manner.
  • Chk2 is also endogenously activated in a large fraction of tumors, and therefore might be critical for tumor growth.
  • a Compounds inhibits Chk2 activty two times, three times, four times, ten times, 20 times, 25 times or more than it inhibits Chkl activity. Inhibition can be determined using Chk2 and Chkl activity assays known in the art or set forth herein. 5.4 METHODS FOR MAKING COMPOUNDS
  • the Compounds have utility as pharmaceuticals to treat or prevent disease in animals and/or humans. Further, the Compounds are active against protein kinases, such as Chk2, including those involved in cancer, hypoxia, diabetes, stroke, and autoimmune disease. Accordingly, provided herein are many uses of the Compounds, including the treatment or prevention of those diseases set forth below.
  • the methods provided herein comprise the administration of a Compound to a patient in need thereof.
  • autoimmune conditions that Compounds are useful for treating or preventing include, but are not limited to, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, multiple sclerosis, lupus, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, Grave's disease and diabetes ⁇ e.g., Type I diabetes).
  • Particular representative diabetic conditions that Compounds are useful for treating or preventing include, but are not limited to Type II diabetes, Type I diabetes, slow- onset Type I diabetes, diabetes insipidus (e.g., neurogenic diabetes insipidus, nephrogenic diabetes insipidus, dipsogenic diabetes insipidus, or gestagenic diabetes insipidus), diabetes mellitus, gestational diabetes mellitus, polycystic ovarian syndrome, maturity-onset diabetes, juvenile diabetes, insulin-dependant diabetes, non-insulin dependant diabetes, malnutrition-related diabetes, ketosis-prone diabetes, pre-diabetes (e.g., imparied glucose metabolism), cystic fibrosis related diabetes, hemochromatosis and ketosis-resistant diabetes.
  • diabetes insipidus e.g., neurogenic diabetes insipidus, nephrogenic diabetes insipidus, dipsogenic diabetes insipidus, or gestagenic diabetes insipidus
  • provided herein are methods for the treatment or prevention of hypoxia comprising administering a Compound to a patient.
  • methods for the treatment or prevention of stroke comprising administering a Compound to a patient.
  • methods for the treatment or prevention of Coffin-Lowry syndrome comprising administering a Compound to a patient.
  • the Compound is of formula (VIII) or (IX).
  • Representative cancers that the Compounds are useful for treating or preventing include, but are not limited to, cancers of the head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder, uterine, cervix, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, and brain or central nervous system.
  • Cancers within the scope of the methods provided herein include those associated with one or more kinases from the Chk kinase family, kinases from the MEK kinase family, kinases from the src kinase family, kinases from the RSK kinase family, kinases from the CDK family, kinases from the MAPK kinase family, and tyrosine kinases such as Fes, Lyn, and Syk kinases, and mutants or isoforms thereof.
  • a kinase including, but are not limited to, Chk2 kinase, RSK2, tyrosine-protein kinase (SYK), tyrosine-protein kinase (ZAP-70), protein tyrosine kinase 2 beta (PYK2), focal adhesion kinase 1 (FAK), B lymphocyte kinase (BLK), hemopoietic cell kinase (HCK), v- yes-1 Yamaguchi sarcoma viral related oncogene homolog (LYN), T cell-specific protein- tyrosine kinase (LCK), proto-oncogene tyrosine-protein kinase (YES), proto-oncogene tyrosine-protein kinase (SRC), proto-oncogen
  • a disease or disorder associated with the modulation, for example inhibition, of serine/threonine kinases or related molecules including, but not limited to, cyclin- dependent kinase 7 (CDK7), rac serine/threonine protein kinase, serine-threonine protein kinase n (PKN), serine/threonine protein kinase 2 (STK2), zipper protein kinase (ZPK), protein-tyrosine kinase (STY), bruton agammaglobulinemia tyrosine kinase (BTK), mkn28 kinase, protein kinase, x-linked (PRKX), elk-related tyrosine kinase (ERK), ribosomal protein s6 kinase, 90 kd, polypeptide 3 (RPS6KA3),
  • CDK7 cyclin- dependent kinase 7
  • MAP kinase including, but not limited to, mitogen-activated protein kinase 3
  • MAPK3 p44erkl, p44mapk, mitogen-activated protein kinase 3 (MAP kinase 3; p44), ERKl, PRKM3, P44ERK1, P44MAPK, mitogen-activated protein kinase 1 (MAPKl), mitogen-activated protein kinase kinase 1 (MEKl), MAP2K1 protein tyrosine kinase ERK2, mitogen-activated protein kinase 2, extracellular signal-regulated kinase 2, protein tyrosine kinase ERK2, mitogen-activated protein kinase 2, extracellular signal-regulated kinase 2, ERK, p38, p40, p41, ERK2, ERTl, MAPK2, PRKMl, PRKM2, P42MAPK, p41mapk, mitogen-activated protein kinase 7 (MAPK7), BMKl kinase, extracellular
  • cancers and related disorders that can be treated or prevented by methods and compositions provided herein include but are not limited to the following: Leukemias such as but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblasts, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplastic syndrome (or a symptom thereof such as anemia, thrombocytopenia, neutropenia, bicytopenia or pancytopenia), refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB in transformation (RAEB-T), preleukemia and chronic myelomonocytic leukemia (CMML), chronic leukemias such as but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic
  • cancers include myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma and papillary adenocarcinomas (for a review of such disorders, see Fishman et al., 1985, Medicine, 2d Ed., J.B.
  • carcinoma including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin; including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Berketts lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias and promyelocytic leukemia
  • cancers caused by aberrations in apoptosis would also be treated by the methods and compositions disclosed herein.
  • Such cancers may include but not be limited to follicular lymphomas, carcinomas with p53 mutations, hormone dependent tumors of the breast, prostate and ovary, and precancerous lesions such as familial adenomatous polyposis, and myelodysplastic syndromes.
  • malignancy or dysproliferative changes (such as metaplasias and dysplasias), or hyperproliferative disorders, are treated or prevented in the ovary, bladder, breast, colon, lung, skin, pancreas, or uterus.
  • sarcoma, melanoma, or leukemia is treated or prevented.
  • the methods and compositions provided herein are also useful for administration to patients in need of a bone marrow transplant to treat a malignant disease ⁇ e.g., patients suffering from acute lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome ("preleukemia"), monosomy 7 syndrome, non-Hodgkin's lymphoma, neuroblastoma, brain tumors, multiple myeloma, testicular germ cell tumors, breast cancer, lung cancer, ovarian cancer, melanoma, glioma, sarcoma or other solid tumors), those in need of a bone marrow transplant to treat a non-malignant disease (e.g., patients suffering from hematologic disorders, congenital immunodeficiences, mucopolysaccharidoses, lipidoses, osteoporosis, Langerhan's
  • the myeloproliferative disorder is polycythemia rubra vera; primary thrombocythemia; chronic myelogenous leukemia; acute or chronic granulocytic leukemia; acute or chronic myelomonocytic leukemia; myelofibro-erythroleukemia; or agnogenic myeloid metaplasia.
  • STI-571 or GleevecTM kinase inhibitors
  • methods for the treatment of cancer or tumors resistant to other kinase inhibitors such as imatinib mesylate (STI-571 or GleevecTM) treatment, comprising administering to a patient in need thereof an effective amount of a Compound or a composition thereof.
  • methods for the treatment of leukemias including, but not limited to, gastrointestinal stromal tumor (GIST), acute lymphocytic leukemia or chronic myelocytic leukemia resistant to imatinib mesylate (STI-571 or GleevecTM) treatment, comprising administering to a patient in need thereof an effective amount of a Compound or a composition thereof.
  • GIST gastrointestinal stromal tumor
  • STI-571 or GleevecTM chronic myelocytic leukemia resistant to imatinib mesylate
  • kits for treating or preventing a disease or disorder treatable or preventable by inhibiting Chk2 or the ATM-Chk2 pathway comprising administering an effective amount of a Compound to a patient in need of the treating or preventing.
  • diseases which are treatable or preventable by inhibiting Chk2 or the ATM-Chk2 pathway include, but are not limited to, cancer, hypoxia, diabetes, stroke, autoimmune disease, and other specific diseases and conditions disclosed herein.
  • provided herein are methods for treating or preventing a disease or disorder treatable or preventable by inhibiting RSK2 or the RSK2 pathway, comprising administering an effective amount of a Compound to a patient in need of the treating or preventing.
  • the Compound is of formula (VIII) or (IX).
  • Particular diseases which are treatable or preventable by inhibiting RSK2 or the RSK2 pathway include, but are not limited to, breast cancer, prostate cancer, osteosarcoma and Coffin-Lowry syndrome.
  • kits for the treatment or prevention of chemotherapy induced hair loss comprising administering to a patient in need thereof (such as a patient who has undergone, is undergoing, or is scheduled to undergo chemotherapy) an effective amount of a Compound or a composition thereof.
  • a patient in need thereof such as a patient who has undergone, is undergoing, or is scheduled to undergo chemotherapy
  • chemotherapy stimulates apoptosis in hair follicles, which results in hair loss.
  • p53 is thought to be essential to this process ⁇ see, e.g., Botchkarev et al, 2000, Cancer Res. 60(18):5002-5006).
  • a patient in need of administration e.g., for treatment or prevention of a disease or disorder
  • a Compound by determining the level of a marker (e.g., the expression level or activity of Chk2, RSK2, p53, E2F1, PML, a Cd25 phosphatase, Brcal or a kinase disclosed herein) and administering an effective amount of a Compound to the patient.
  • a marker e.g., the expression level or activity of Chk2, RSK2, p53, E2F1, PML, a Cd25 phosphatase, Brcal or a kinase disclosed herein
  • tissue e.g., non- cancerous tissue
  • methods for protecting normal tissue comprising identifying a patient having tissue in need of such protection and administering to the patient an amount of a Compound effective to protect normal tissue.
  • the tissue is protected from becoming cancerous or metastases are reduced or avoided.
  • apopstosis in a normal cell e.g., non-cancerous cell
  • identifying a patient having one or more cells in need of such prevention or reduction and administering to the patient an amount of a Compound effective to prevent or reduce apoptosis in a normal cell.
  • a methods for sensitizing a tumor, a cancer cell or cancerous tissue to an anticancer agent, anticancer treatment (e.g., radiation therapy) or a DNA targeted agent comprising administering a patient who has cancer or a tumor an amount of a Compound effective to sensitize the cancer or tumor to an anticancer agent, anticancer treatment or a DNA targeted agent.
  • the Compounds and the anticancer agent, anticancer treatment or a DNA targeted agent are administered in combination (e.g., simultaneously or sequentially).
  • the Compounds and the anticancer agent, anticancer treatment or a DNA targeted agent provide a synergistic effect when administered to a ptient.
  • Chemotherapeutic agents that Compounds are useful in combination with include, but are not limited to, toposimoerase inhibitors, antiangiogenesis agents, selective estogen-receptor modulators (SERMs), aromatase inhibitors and DNA-targeted agents.
  • SERMs selective estogen-receptor modulators
  • chemotherapeutic agents that Compounds are useful in combination with include, but are not limited to, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedef
  • anti-cancer drugs include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5- ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin;
  • ALL-TK antagonists altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1 ; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1 ; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat;
  • BCR/ABL antagonists benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta- alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-
  • cartilage derived inhibitor cartilage derived inhibitor
  • carzelesin casein kinase inhibitors (ICOS)
  • cell-cycle inhibitors e.g., flavopiridol A, tryprostatin B, pl9ink4D
  • cyclin-dependent kinase inhibitors e.g., roscovitine, olomucine and purine analogs
  • MAP kinase inhibitors e.g., MAP kinase inhibitors
  • CNI- 1493 castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dex
  • plasminogen activator inhibitor platinum complex; platinum compounds; platinum- triamine complex; porfimer sodium; porf ⁇ romycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase
  • kinase C inhibitor protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; retinoic acid (e.g., 9-cis RA); histone deacetylase inhibitors (e.g., sodium butyrate, suberoylanilide hydroxamic acid); TRAIL; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-
  • GAP inhibitor retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes;
  • RII retinamide RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl ; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1 ; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1 ; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive va
  • a substrate e.g., p53, E2F1, or PML
  • a normal cell e.g., non-cancerous cell
  • a protein e.g., a Cdc25 phosphatase
  • methods for modulating comprising identifying a patient in need of such modulation and administering to the patient an amount of a Compound effective to modulate the protein.
  • Chk2 phosphorylation is inhibited or down- regulated.
  • the Compounds can be administered to a patient orally or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions and syrups.
  • Suitable formulations can be prepared by methods commonly employed using conventional, organic or inorganic additives, such as an excipient (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), a binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose or starch), a disintegrator (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), a flavoring agent (e.g., citric acid, menthol, glycine or orange powder
  • the effective amount of the Compounds in the pharmaceutical composition may be at a level that will exercise the desired effect; for example, about 0.005 mg/kg of a patient's body weight to about 10 mg/kg of a patient's body weight in unit dosage for both oral and parenteral administration.
  • a pharmaceutical composition is a composition suitable for administration to a patient, such as a human.
  • the dose of a Compound to be administered to a patient is rather widely variable and can be subject to the judgment of a health-care practitioner.
  • the Compounds can be administered one to four times a day in a dose of about 0.005 mg/kg of a patient's body weight to about 10 mg/kg of a patient's body weight in a patient, but the above dosage may be properly varied depending on the age, body weight and medical condition of the patient and the type of administration.
  • the dose is about 0.01 mg/kg of a patient's body weight to about 5 mg/kg of a patient's body weight, about 0.05 mg/kg of a patient's body weight to about 1 mg/kg of a patient's body weight, about 0.1 mg/kg of a patient's body weight to about 0.75 mg/kg of a patient's body weight or about 0.25 mg/kg of a patient's body weight to about 0.5 mg/kg of a patient's body weight.
  • one dose is given per day.
  • the amount of the Compound administered will depend on such factors as the solubility of the active component, the formulation used and the route of administration.
  • kits for the treatment or prevention of a disase or disorder disclosed herein comprising the administration of about 0.375 mg/day to about 750 mg/day, about 0.75 mg/day to about 375 mg/day, about 3.75 mg/day to about 75 mg/day, about 7.5 mg/day to about 55 mg/day or about 18 mg/day to about 37 mg/day of a Compound to a patient in need thereof.
  • kits for the treatment or prevention of a disase or disorder disclosed herein comprising the administration of about 1 mg/day to about 1200 mg/day, about 10 mg/day to about 1200 mg/day, about 100 mg/day to about 1200 mg/day, about 400 mg/day to about 1200 mg/day, about 600 mg/day to about 1200 mg/day, about 400 mg/day to about 800 mg/day or about 600 mg/day to about 800 mg/day of a Compound to a patient in need thereof.
  • the methods disclosed herein comprise the administration of 400 mg/day, 600 mg/day or 800 mg/day of a Compound to a patient in need thereof.
  • unit dosage formulations that comprise between about 1 mg and 200 mg, about 35 mg and about 1400 mg, about 125 mg and about 1000 mg, about 250 mg and about 1000 mg, or about 500 mg and about 1000 mg of a Compound.
  • unit dosage formulation comprising about 100 mg or 400 mg of a Compound.
  • unit dosage formulations that comprise 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of a Compound.
  • a Compound can be administered once, twice, three, four or more times daily.
  • doses of 600 mg or less are administered as a a once daily dose and doses of more than 600 mg are administered twice daily in an amount equal to one half of the total daily dose.
  • a Compound can be administered orally for reasons of convenience.
  • a Compound when administered orally, a Compound is administered with a meal and water.
  • the Compound is dispersed in water or juice (e.g., apple juice or orange juice) and administered orally as a suspension.
  • the Compound can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ears, nose, eyes, or skin.
  • the mode of administration is left to the discretion of the health-care practitioner, and can depend in-part upon the site of the medical condition.
  • compositions comprising an effective amount of a Phenyl and a pharmaceutically acceptable carrier or vehicle, wherein a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof.
  • the composition is a pharmaceutical composition.
  • the compositions can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories and suspensions and the like.
  • compositions can be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit, which may be a single tablet or capsule or convenient volume of a liquid.
  • the solutions are prepared from water-soluble salts, such as the hydrochloride salt.
  • all of the compositions are prepared according to known methods in pharmaceutical chemistry.
  • Capsules can be prepared by mixing a Compound with a suitable carrier or diluent and filling the proper amount of the mixture in capsules.
  • the usual carriers and diluents include, but are not limited to, inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
  • Tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
  • Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium
  • a lubricant might be necessary in a tablet formulation to prevent the tablet and punches from sticking in the die.
  • the lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
  • Tablet disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose, for example, can be used as well as sodium lauryl sulfate. Tablets can be coated with sugar as a flavor and sealant, or with film-forming protecting agents to modify the dissolution properties of the tablet. The compositions can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation.
  • the effect of the Compound can be delayed or prolonged by proper formulation.
  • a slowly soluble pellet of the Compound can be prepared and incorporated in a tablet or capsule, or as a slow-release implantable device.
  • the technique also includes making pellets of several different dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even the parenteral preparations can be made long-acting, by dissolving or suspending the Compound in oily or emulsified vehicles that allow it to disperse slowly in the serum.
  • HPLC HPLC was performed on Rainin SD-300 or Varian ProStar equipped with a single wavelength UV detector at 214 nm and linear gradients. Analytical HPLC was performed on a Varian C 18 column (microsorb 60-8, 4.6 x 250 mm) at a flow rate of 1 mL/min. Semi-preparative HPLC was performed on a Varian Ci 8 column (microsorb 60-8, 10.0 x 250 mm) at a flow rate of 5 mL/min. Preparative HPLC was routinely performed on a Varian Cj 8 column (microsorb 60-8, 21.4 x 250 mm) at a flow rate of 20 mL/min.
  • the solvent system used on linear gradients was water with 0.075% TFA (solvent A) vs Acetonitrile with 0.075% TFA (solvent B).
  • Silica gel used in flash column chromatography was obtained from Sorbent Technologies (Atlanta, GA).
  • Analytical thin-layer chromatography (TLC) was carried out using Silica Gel 60 F254 precoated plates G/UV254 plates (Merck, 0.25 mm thickness). TLC R f values are reported. Visulization was accomplished by irradiation with a UV lamp and /or staining with Ceric ammonium molybdate (CAM) solution.
  • LC-MS spectra were taken on Thermo Finnigan Navigator LC/MS-ESI or APCI.
  • 13 C NMR can be used to determine EIZ stereochemistry of Compounds.
  • Reports in the literature demonstrate that the chemical shift of E and Z Dimethyl carbons in a guanidinyl hydrazone are more than 10 ppm apart (Gyorgydeak, Z.; Holzer, W.; Mauster, K. Monatsh. Chem. 1999, 130, 899-913; G ⁇ nitzer, E.;fulnessl, G.; Wagner, U. Eur. J. Pharm. 5c/.2002, 15, 49-61). [00270] Method A (urea linkers)
  • aminoguanidine hydrochloride 212 mg, 1.92 mmol, 4.0 eq
  • p-toluenesulphonic acid monohydrate 328 mg, 3.60 mmol, 4.4 eq
  • the urea intermediate was prepared from 4-acetylphenyl isocyanate and 4'- amino acetophenone by following Method A step (i). To a solution of the urea in anhydrous MeOH (5 mL) was added 2-pyridylhydrazidine (1.5 eq) and para toluenesulphonic acid monhydrate (5eq). The reaction was refluxed for 6-7 min, then rapidly cooled to room temperature. The MS showed the mono-substituent (m/z 414) and disubstituent (m/z 533). Then aminoguanidine hydrochloride (1.0 eq) was added to the reaction mixture and the solution refluxed for another 6-7 min at 9O°C.
  • the urea intermediate was prepared from 4-acetylphenyl isocyanate and 4'- amino acetophenone by following Method A step (i). To a solution of the urea in anhydrous MeOH (5 mL) was added 2-hydrazino-2-imidazoline hydrobromide (1.5 eq) and para toluenesulphonic acid monhydrate (5eq). The reaction was first refluxed for 10 min, then aminoguanidine hydrochloride (1.0 eq) was added to the reaction mixture and refluxed for another 6-7 min at 9O°C. The crude products were purified and isolated by reverse phase HPLC.
  • Example 6.17 Synthesis of Compound 19 [00312] 5-Methoxy-1H-indole-2-carboxlic acid and 4'-aminoacetophenone were combined according to Method B (steps (i) and (ii)), to obtain the product. t R 28.0 min (15-
  • Example 6.19 Synthesis of Compound 22 [00316] 7-nitro-1H-indole-2-carboxlic acid and 4'-aminoacetophenone were combined according to Method B (steps (i) and (ii)), to obtain the product, t R 16.0 min (20-
  • Example 6.32 Synthesis of Compound 88
  • 6-Acetylamino-l H-indole-2-carboxylic acid and 4'-aminoacetophenone were combined according to Method B (steps (i) and (U)), to obtain the product after HPLC purification.
  • Example 6.37 Synthesis of Compound 94
  • 6-Chloro-l H-indole-2-carboxylic acid and 4'-aminoacetophenone were combined according to Method B (steps (i) and (ii)), to obtain the product after HPLC purification.
  • Example 6.38 Synthesis of Compound 99
  • Example 6.44 Synthesis of Compound 101 [00366] 5 -Acetyl- 1H-indole-2-carboxylic acid and 6-amino-quinoline were combined according to Method B (steps (i) and (U)) to obtaine the pure product after HPLC purification. t R 13.77 min (10-50% CH 3 CN in H 2 O, 20 min); MS (m/z) 386(MH + )
  • Example 6.53 Synthesis of Compound 115 [00384] 5- Acetyl- 1 H-indole-2-carboxylic acid and 4-Amino-benzamide were combined according to Method B (steps (i) and (ii)) to obtaine the pure product after HPLC purification. t R 16.99 min (10-40% CH 3 CN in H 2 O, 20 min); MS (m/z) 378(MH + ).
  • Example 6.60 Synthesis of Compound 116 [00400] 1,3-Bis-(4-acetyl-phenyl)-urea, made from 4-acetyl phenylisocyanate and 4- acetyl phenylamine, and N-hydroxy-N'-aminoguanidine PTSA salt, prepared as described in the literature (A. W. Tai, E. J. Lien, E. C. Moore, Y. Chun, and J. Roberts J. Med. Chem.
  • Example 6.64 Synthesis of Compound 77 [00408] 7-Amino-1H-indole-2-carboxylic acid and 4-amino acetophenone were combined according to Method B (steps (i) and (U)) to obtain the pure product after HPLC purification.
  • Example 6.70 Synthesis of Compound 87 [00420] 5-Fluoro-1H-indole-2-carboxylic acid and 4-aminoacetophenone were combined according to Method B (steps (i) and (U)) to obtain the pure product after HPLC purification: t R 13.49 min (20-65% CH 3 CN in H 2 O, 15 min); MS (m/z) 353(MH + ). [00421] Example 6.71; Synthesis of Compound 90
  • Example 6.73 Synthesis of Compound 96 [00426] 7-Nitro-1H-indole-2-carboxylic acid and 5-Amino-indanone were combined according to Method B (steps (i) and (U)) to obtain the pure product after HPLC purification: t R 18.62 min (10-65% CH 3 CN in H 2 O, 20 min); MS (m/z) 392(MH + ). [00427] Example 6.74: Synthesis of Compound 98
  • Example 6.78 Synthesis of Compound 107 [00436] 3H-Benzo[e]indole-2-carboxylic acid and 4-aminoacetophenone were combined according to Method B (steps (i) and (H)) to obtain the pure product after HPLC purification: t R 15.75 min (20-80% CH 3 CN in H 2 O, 20 min); MS (m/z) 385(MH + ).
  • Example 6.79 Synthesis of Compound 126 [00438] 5-Acetyl-1H-indole-2-carboxylic acid and 6-amino isoquinoline were combined according to Method B (steps (i) and (ii)) to obtained the pure product after HPLC purification. t R 16.67 min (10-40% CH 3 CN in H 2 O, 20 min); MS (m/z) 386(MH + ).
  • Compounds can be screened for Chk2 inhibitory activity using a high- throughput screening assay based in the immobilized metal ion affinity-based fluorescence polarization (IMAP) assay developed by Molecular Devices.
  • IMAP immobilized metal ion affinity-based fluorescence polarization
  • This assay is based on the high affinity binding of phosphate by immobilized metal (Mill) coordination complexes on nanoparticles.
  • a fluorescein-labeled peptide substrate is used as the substrate for the kinase activity of Chk2 in the assay.
  • the IMAP binding reagent stops the kinase reaction.
  • the binding of the binding reagent results in a change in the rate of molecular motion of the peptide and causes an increase in the fluorescence polarization value observed for the fluorescein label attached to the end of the peptide.
  • inhibition of Chk2 would result in a decrease in fluorescence polarization compared to control.
  • 6xHis-Chk2 can be expressed and purified using the following protocol.
  • Day 1 Add 1 ⁇ l of purified Chk2 plasmid to one vial of BL21 Star cells (Invitrogen); leave on ice for 15-30 minutes; heatshock at 42°C for 30 seconds; return to ice for 2-3 minutes; add 250 ⁇ l SOC and shake at 37°C for one hour; divide the bacterial suspension among four LB plates with 50 ⁇ g/ml ampicillin (if there are pools of media on the plates, place them, uncovered, in tissue culture hood for about 15 minutes to dry); incubate plates overnight at 37°C.
  • BL21 Star cells Invitrogen
  • Day 3 Place one tube of frozen cell suspension in 37°C water bath to thaw; shake frequently and minimize warming of sample; place thawed tube of lysate in wate ⁇ ice bath; sonicate 6x for 30 sec; allow the sample to cool on ice for at least one minute between pulses (more if needed); add imidazole to 10 mM (100 ⁇ l for 20 ml of lysate); centrifuge at 50,000 x g for 30 minutes at 4°C; place clean 50 ml centrifuge tube on ice to chill; if crude column is not used, attach 0.45 ⁇ m SFCA filter to 30ml syringe from which plunger has been removed, gently decant supernatant from centrifuge tube into syringe barrel, and carefully push lysate through filter into pre-chilled centrifuge tube, changing filters as necessary; place centrifuge tube in holder on FPLC and insert sample line Sl ; run protocol (Equilibrate
  • a Compound is supplied at 1 mM in 0.5 ⁇ l DMSO on 384 well plates (such as Greiner or Corning). After thawing, 5 ⁇ l DMSO is added to the drug plate. The drug plate is then incubated for 10 minutes to solubilize the Compound. An additional 19.5 ⁇ l of reaction buffer (10X stock prepared using 100 mM Tris-HCl, 100 mM MgCl 2 , 1% BSA, pH 7.2, stored at 4°C) + 1 mM DDT is added to bring the Compound to 4X final concentration. A posititve control is also prepared at 4X final concentration.
  • control wells are used: less enzyme control (all reagents except enzyme; 5 ⁇ l/well), less Compound control (all reagents except Compound; 5 ⁇ l/well), positive control (all reagents plus staurosporine at a final concentration of 5 ⁇ M; 5 ⁇ l/well).
  • Reagents are then added in the following order to give the following final concentration: 2.5 ⁇ l ATP/Chk2tide (Molecular Devices) (10 ⁇ M/100nM final concentration), 1.25 ⁇ l Compound (5 ⁇ M final concentration inf 5.5% DMSO), and 1.25 ⁇ l Chk2 (1 :500, 2.4 ⁇ g/mL final concentration). [00458] Plates are covered and incubated at room temperature for 60 minutes. [00459] IMAP binding reagent (Molecular Devices) is diluted 1 :400 into binding buffer (Molecular Devices). 15 ⁇ l of this solution is then added to all wells and the plates are covered and incubated for 30 minutes.
  • Plates are read using a Tecan Ultra under the fluorescence polarization mode. Gain is set to the less enzyme and less Compound wells for each plate. Excitation 485 run, emmission 535 nm, Z position 12519 and flashes 5 are used as settings. Raw data from the Tecan reader is imported into an access database for analysis.
  • This assay is based on using ⁇ 32 P-labeled ATP to mediate phosphorylation of the target substrate and autophosphorylation of Chk2. Reactions are performed at 30°C for appropriate times, then the samples have 2X SDS loading buffer added to quench the reaction. Samples are boiled for about 5 minutes and tehn subjected to SDS-PAGE. [00463] Staurosporine is used as a postitive control to confirm Chk2 inhibition.
  • Example 6.86 RSK2 Assay
  • Kinase activity was assayed using recombinant RSK2 enzyme, which was prepared as previously described (Clark et al, 2001 , EMBO J. 20:3484-349).
  • Fluoroscein- labeled peptide substrate for RSK2 and IMAPTM beads for capturing phosphorylated product were purchased from Molecular Devices. These reagents were combined in assay buffer containing 10 ⁇ M ATP and test Compounds in 384-well Greiner (Matrical) black plates (20 ⁇ L final volume). Phosphorylated substrate was detected by fluorescence polarization spectroscopy after binding to IMAPTM beads.

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Abstract

La présente invention concerne des composés présentant la structure suivante : formule (I) dans laquelle A, L, X et le cycle B sont tels que définis ici, des compositions contenant une quantité efficace du composé et des procédés destinés à traiter ou à prévenir le cancer, l'hypoxie, le diabète, les accidents vasculaires cérébraux, les maladies auto-immunes ou des états pathologiques susceptibles d'être traités ou prévenus par l'inhibition de Chk2, de la voie ATM-Chk2 ou de RSK2, consistant à administrer une quantité efficace d'un composé à un patient en ayant besoin.
PCT/US2008/007181 2007-06-12 2008-06-09 Inhibiteurs de kinases, leurs compositions et procédés d'utilisation WO2008156573A1 (fr)

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US9278089B2 (en) 2011-10-26 2016-03-08 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Method of treating HCV infection with a small molecule CHK2 inhibitor
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